DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

FOOD AND DRUG ADMINISTRATION

 

CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

 

 

 

 

ANTI-INFECTIVE DRUGS ADVISORY

 

COMMITTEE (AIDAC) MEETING

 

 

 

Discussion of Issues Related to Clinical

Trial Design and Analysis in Studying Bacteremia

Due to Staphylococcus aureus and

Catheter Related Bacteremia

 

 

 

 

 

 

 

 

 

 

 

 

 

Thursday, October 14, 2004

 

8:20 a.m.

Hilton Gaithersburg

The Ballroom

620 Perry Parkway

Gaithersburg, Maryland


 

PARTICIPANTS

 

James E. Leggett, Jr., M.D., Chair

Shalini Jain, PA-C, MBA, Executive Secretary

 

MEMBERS

 

         Alan S. Cross, M.D.

         Celia J. Maxwell, M.D.

         Jan E. Patterson, M.D.

         Joan F. Hilton, Sc.D., MPH

         John S. Bradley, M.D.

         Donald M. Poretz, M.D.

         Samuel D. Maldonado, M.D., MPH

           (Industry Representative)

         John E. Edwards, Jr., M.D.

 

CONSULTANTS, SPECIAL GOVERNMENT EMPLOYEES (VOTING)

 

         Thomas R. Fleming, Ph.D.

         Christopher A. Ohl, M.D.

         L. Barth Reller, M.D.

         Nathan M. Theilman, M.D., MPH

 

CONSULTANT, FEDERAL EMPLOYEE (VOTING)

 

         Patrick R. Murray, Ph.D.

 

FDA

 

         Mark Goldberger, M.D.

         Sumathi Nambiar, M.D.

         John H. Powers, M.D.

         Alfred Sorbello, D.O.

         Janice Soreth, M.D.

C O N T E N T S

 

Call to Order and Opening Remarks:

         James E. Leggett, Jr., M.D.     5

 

Conflict of Interest Statement:

         Shalini Jain, PA-C, MBA         8

 

Opening Comments:

         Janice Soreth, M.D.            11

 

Regulatory History of Bacteremia Indications:

         Alfred Sorbello, D.O.          23

 

Questions from Committee                40

 

Epidemiology of S. aureus Bacteremia:

         Sumathi Nambiar, M.D.          55

 

Questions from Committee                74

 

Microbiological Considerations in Diagnosing

S. aureus Bacteremia:

         Patrick Murray, Ph.D.          82

 

Questions from Committee               103

 

Open Public Hearing--Extra Session     109

         Francis P. Tally, M.D.,

           Cubist Pharmaceuticals Inc.

 

Clinical Trials Issues with Studies of S. aureus

Bacteremia:

         John H. Powers, M.D.          131

 

Questions from Committee               173

 

Open Public Hearing    208

         Tim Henkel, M.D., Ph.D., Vicuron

         Pharmaceuticals               209

         Charles Knirsch, M.D., MPH, Pfizer

         Pharmaceuticals               222

        

         C O N T E N T S (Continued)

 

David Shlaes M.D., Ph.D., Idenix

Pharmaceuticals                        242

 

Issues in Studying Catheter-Related Bacteremia:

         Janice Pohlman, M.D.          247

 

Questions from Committee               269

 

Questions to Committee and Discussion 272

 

Summary  366


P R O C E E D I N G S

Call to Order and Opening Remarks

         DR. LEGGETT:  Good morning.  Today we are gathered to discuss issues related to clinical-trial design and analysis in studying bacteremia due to Staphylococcus aureus as well as issues related to clinical-trial design or analysis in studying catheter-related bacteremia.

         It is going to be, I hope, not a terribly eventful day but eventful, nonetheless.  I think that the problem that we are faced with, as clinicians, I faced on Friday when I was asked to see two patients, one a recently end-stage renal-disease patient with diabetes who has had three MRSA hemodialysis catheter infections since July when she started dialysis requiring the removal of the catheter and, at the same time, was called to see a patient because they had Gram-positive cocci in clusters from their one of two blood cultures and it turned out to be coagulate-negative Staph and who cared.

         So I think that is going to be sort of the crux of a lot of the problems today.

         To get started, why don't we go around the table and have everyone introduce themselves.

         DR. MAXWELL:  I'm Celia Maxwell, the Assistant Vice President for Health Sciences at Howard University, an adult infectious diseases specialist.

         DR. BRADLEY:  I am John Bradley, Pediatric Infectious Diseases, from Children's Hospital in San Diego.

         DR. OHL:  Chris Ohl, Section on Infectious Diseases, Wake Forest University School of Medicine.

         DR. HILTON:  Joan Hilton.  I am on the Biostatistics Faculty at University of California, San Francisco.

         DR. MURRAY:  Pat Murray, Director of Microbiology at the NIH Clinical Center.

         DR. RELLER:  Barth Reller, Division of Infectious Diseases and International Health and Director of Clinical Microbiology, Duke University Medical Center.

         DR. LEGGETT:  Jim Leggett, Infectious Diseases, Providence Portland Medical Center and the Oregon Health and  Sciences University.

         DR. CROSS:  Alan Cross, Center for Vaccine Development, University of Maryland.

         DR. FLEMING:  Thomas Fleming, Department of Biostatistics, University of Washington.

         DR. MALDONADO:  Sam Maldonado, Global and Regulatory Affairs, Johnson & Johnson.  I am the industry representative to this committee.

         DR. PATTERSON:  Jan Patterson, Medicine Infectious Diseases, University of Texas Health Science Center, San Antonio and South Texas Veterans Healthcare System.

         DR. THEILMAN:  Nathan Theilman, Division of Infectious Diseases and International Health, Duke University Medical Center.

         DR. PORETZ:  Donald Poretz, Infectious Diseases in Fairfax, Virginia.

         DR. NAMBIAR:  Sumathi Nambiar, Division of Anti-Infective Drug Products, FDA.

         DR. SORBELLO:  Fred Sorbello, Medical Officer, FDA.

         DR. POWERS:  John Powers, Lead Medical Officer for Antimicrobial Drug Development and Resistance Initiatives in ODE IV at FDA.

         DR. SORETH:  Good morning.  I am Janice Soreth, the Division Director for Anti-Infectives.  Let me take the opportunity to introduce in absentia our Office Director, Dr. Mark Goldberger, who is on his way.  But another person who is actually here and who directs a sister division, that of Special Pathogens and Immunologic Drugs which also regulates antibiotic development.  That would be Dr. Renata Albrecht who sits behind me here.

         MS. JAIN:  I am Shalini Jain, Executive Secretary for the Anti-Infective Drugs Advisory Committee.

Conflict of Interest Statement

         MS. JAIN:  Before we begin the meeting, I need to read a conflict-of-interest statement.  The following announcement addresses the issue of conflict of interest issues associated with this meeting and is made a part of the record to preclude even the appearance of such.

         Based on the agenda, it has been determined that the topics of today's meeting are issues of broad applicability and there are no products being approved.  Unlike issues before a committee in which a particular product is discussed, issues of broader applicability involve many industrial sponsors in academic institutions.

         All Special Government Employees have been screened for their financial interests as they may apply to the general topics at hand.  To determine if any conflict of interest existed, the agency has reviewed the agenda and all relevant financial interests as reported by the meeting participants.

         The Food and Drug Administration has granted general-matters waivers to the Special Government Employees participating in this meeting who require a waiver until Title 18 United States Code Section 208.  A copy of waiver statements may be obtained by submitted a written request to the agency's Freedom of Information Office, Room 12A-30 of the Parklawn Building.

         Because general topics impact so many entities, it is not practical to recite all potential conflicts of interest as they may apply to each member, consultant and guest speaker.  FDA acknowledges that there may be potential conflicts of interest but, because of the general nature of the discussions before the committee, these potential conflicts are mitigated.

         With respect to FDA's invited industry representative, we would like to disclose that Dr. Samuel Maldonado is participating in this meeting as a non-voting industry representative acting on behalf of regulated industry.  Dr. Maldonado's role on this committee is to represent industry interests in general and not any one particular company.  Dr. Maldonado is employed by Johnson & Johnson.

         In the event that the discussions involve any other products or firms not already on the agenda for which FDA participants has a financial interest, the participants' involvement and their exclusion will be noted for the record.

         With respect to all other participants, we ask, in the interest of fairness, that all persons making statements or presentations disclose any current or previous financial involvement with any firm whose products they may wish to comment upon.

         Thank you.

         DR. LEGGETT:  Janice, would you like to start?

Opening Comments

         DR. SORETH:  Good morning, Dr. Leggett and special thanks for the academic quarter this morning, members of the advisory committee, FDA and industry colleagues and other members of the audience.

         (Slide.)

         I would like to begin today's talks by telling you what we are going to talk about today followed by actually talking about it, then summarizing what we already told you as a segue to the discussion.  I promise we will finish before midnight.

         This is the story of blood and guidance going a bit bad, that of bacteremia as an indication.

         (Slide.)

         I am going to take us first through the District of Columbia, Rockville and White Oak--you will understand what I mean in just a moment--followed by a tour, very briefly, of Hollywood, the Washington Redskins, the NHL lockout, Monday morning quarterbacking--that would be the discussion period--and wrapping up with credits.  I promise you I have not yet lost my mind.

         (Slide.)

         We are back in the District of Columbia.  It is pre-1965.  I am in second grade.  We have been talking about bacteremia, sepsis, bacteremic sepsis, septicemia, primary bacteremia and secondary bacteremia for a long, long time, ever since the FDA was solely located in the District.

         As far as the Org chart goes back then, and this is all oral history, we were the Bureau of Biological and Physical Sciences, the Division of Pharmacology and we were a branch, I think, of Antibiotics.  As I said, my knowledge of this era is entirely derivative.

         (Slide.)

         Let's fast-forward to Rockville of the '70s and the '80s where the language for bacteremia and septicemia began to make it into package inserts.  We will hear more about this historical framework and its details through to the 1990s and the present from Dr. Fred Sorbello this morning.

         The Org chart was changing.  We were becoming the Bureau of Biological and Physical Sciences, Division of Pharmacology to the Bureau of Drugs and Biologics, Division of Anti-Infective and, finally, the Center for Drug Evaluation and Research.  I realize only now I forgot to put Crystal City on there because, once we went from the District, we went to Crystal City which is in Virginia and then, ultimately, to Rockville and Gaithersburg, which is where we are now.

         The Division was morphing at the same time.  It was growing.  Back in the '70s and '80s, we were the Division of Anti-Infectives.  We were one entity that took care of regulation of antibiotics, anti-infectives, anti-parasitics, topical antiseptics, dermatologics, ophthalmologics, anti-fungals, T.B. drugs and antivirals.  I am sure I left something out.  Let me know at the break.

         There was a split, then, that happened in the latter '80s.  I think it was about '88 when the development of HIV therapies took off, as it should.  So we split and became the Division of Antiviral Drugs as well as the Division of Anti-Infectives.  The Antiviral therapies together with the Antifungals and the TB drugs, then, went to the Division of Antivirals.

         This is the late '80's, early '90's.

         (Slide.)

         By the time we hit mid-'90's, maybe about 1996, we, as two divisions, were large again.  Portfolios were growing.  So we decided to morph at that point into a third division.  So the Ur-Division, as I like to call it, of Anti-Infectives then became Anti-Infectives, Antivirals and Special Pathogens and Immunologic Drug Products directed by Dr. Renata Albrecht.

         The portfolio from Anti-Infectives of quinolones split off to Special Pathogens.  I believe chronic fatigue and AIDS wasting type of drugs and transplant products and antifungals and antiparasitics also went to Special Pathogens.

         So we are now three divisions under the leadership of Dr. Mark Goldberger.  It is pertinent--the background is pertinent to today because the topics really touch all of us within the office and particularly Anti-Infectives and Special Pathogens.  We need to be careful as we write the music that we sing from the same sheet of music.

         I think more on the history of what we have struggled with as a word, bacteremia, septicemia, will be discussed later today not only by Dr. Fred Sorbello but also, in terms of clinical-trial design considerations by Dr. John Powers, by Dr. Janice Pohlman as well as Dr. Sumathi Nambiar.

         (Slide.)

         As to the future, we are moving in 2005, we are told, to White Oak.  Shalini, correct me if I am wrong, but I think all that AC meetings will take place there.

         MS. JAIN:  Actually no.  They won't be able to actually accommodate the size.

         DR. SORETH:  Wonderful.  Okay.  To be determined later.  Shalini was just saying that we won't necessarily have the AC meetings at White Oak.  It is our combined campus, a dream that we have maintained at FDA for a long, long time.  Some would say a nightmare, but whatever.   It is off New Hampshire around the Beltway for Washingtonians.

         This is the laboratory building.  Our building is off to that side.  I am a little challenged directionally.  I would submit to you that we sincerely hope to have the guidance in this arena tucked away by the time we move to White Oak.  So, see, we have a challenge.

         (Slide.)

         Hollywood, where we are told nothing is impossible, where every scientist should remove the word "impossible" from his lexicon.  Christopher Reeve.  Nothing is impossible.

         (Slide.)

         Except maybe when it comes to the breakdown of skin, invasion of the blood stream and infection of the patient followed by cardiac arrest, heart failure, coma and death, for Superman was no match for a bloodstream infection.

         (Slide.)

         I think our meeting today will highlight that it takes extraordinary individuals to recognize that investment and effort in the discovery of new antibiotics and in the treatments for serious infections, like Staphylococcus aureus bacteremia, are indeed worth it in the long run.  And I know that some of these extraordinary individuals are in this room today.

         They are prescribing physicians.  They are academicians.  They are industry colleagues.  They are FDA colleagues.  They are support staff all of whom have, at heart, the same mission.

         (Slide.)

         So what do the Skins have to do with this?  Well, you have to ask yourself the question what do Joe Gibbs, who is the Head Coach of the Washington Redskins, and the FDA have in common?  I will preface my comments by saying I am a die-hard Eagles fan but it is not why I say this.

         Just like Joe Gibbs, we thought we had put all the right pieces together on the team with the catheter-related blood-stream infection guidance.  That is 1999 and Dr. Janice Pohlman will tell us a lot more about that later today.  And, just like Joe Gibbs, we watched as the monster just wouldn't get up.

         (Slide.)

         We discussed the catheter-related blood-stream infection guidance hereafter known as CRBSI at a 1999 advisory committee meeting.  Most of you were probably not here then because we had a different committee there.  But I know Dr. Barth Reller was there.  The U.S. stats would tell us that roughly there are 200,000 or 400,000 episodes per year.  We should be able to study it.

         Mortality attributable somewhere between 10, 25 percent; we thought a definable case definition--we thought.  Lo and behold, sponsors, many of them, now tell us there are numerous reasons why they have hit the boards.  But I would ask, don't blame it on my heart; blame it on my youth.

         (Slide.)

         The NHL lockout is pertinent here because success, beyond being tied to this year's salary cap, is determined not by knowing where the puck is, rather knowing where the puck is going to be, which is sometimes, maybe often, unpredictable which is probably why they don't want a salary cap in the first place.  But the increasing incidence of Staph aureus bacteremia paralleled by a rise in infective endocarditis, I think, foreshadows where major players need to position themselves to win, to develop effective therapies whose risk/benefit ratio we think we understand so that, ultimately, patients and their prescribing physicians can benefit from this.

         (Slide.)

         The issues for discussion are many.  Dr. John Powers will cover these in great detail.  I have made some excerpts and highlights from his talk that will come later today.  But I want you to bear them in mind as you go through today's discussions and talks.  Should primary bacteremia due to Staph aureus, PBSA, be an indication?  And what exactly would a healthy development program look like?  What patient populations would be included in such a program?

         And, just as importantly, would there be populations that should be excluded, because we are not really sure they have an infection?  Do they have a lab finding?  Should endocarditis due to Staph aureus be a separate indication?

         (Slide.)

         More issues for discussion.  Should we grant a separate catheter-related blood-stream infection indication in its own right?  Does it have merit?  Does it lack merit?  Or, do we fold it into a more general clinical-trial experience and product label under the rubric of primary bacteremia due to Staph aureus or under the rubric of complicated skin infections?

         If we go the separate way, what additional information would you suggest be collected before, or while, treating other serious Staph aureus infections?

         (Slide.)

         Finally, what role do preclinical and early clinical studies play in setting the stage for faster, larger clinical trials?  We are cognizant of the fact that, in many ways, in drug development, as in life, time and money are our enemies.  We sweat the small stuff and we ask you today to do the same.

         How many positive blood cultures are required prior to entry into a primary bacteremia due to Staph aureus clinical trial?

         (Slide.)

         Last, screening patients for admission into these clinical trials appears to be complicated.  Do you have any thoughts or advice for us as to a general approach?

         (Slide.)

         I would like to thank Shalini Jain, our Exec Sec contact and organizer for today's meeting who answered numerous phone calls, E-mails and cell-phone calls way later than anyone should have made them, myself included; our Office Director, Mark Goldberger; John Powers; Ed Cox: and Leo Chan; and, at the Division level, my ever supportive reliable deputy, Lilian Gravrilovich and members of the division, Sumathi Nambiar, Janice Pohlman and Fred Sorbello.

         I will stop there and turn the podium back over to Dr. Leggett.

         DR. LEGGETT:  Thank you.

         Let's move on to the Regulatory History of Bacteremia Indications which will be done by Dr. Sorbello.

Regulatory History of Bacteremia Indications

         DR. SORBELLO:  Good morning.  I am Fred Sorbello, Medical Officer at the Division of Anti-Infective Drug Products at FDA.

         (Slide.)

         My presentation today will focus on the regulatory history of bacteremia and some of the early regulatory history of catheter-related blood-stream infections as labeled blood-stream infection indications.

         (Slide.)

         I wanted to start with an historical time line to help to focus a little bit on the history of the development of this whole issue from a regulatory perspective.  It really began prior to 1992, 1993.  As Dr. Soreth had described, there were various types of terminology that were being used in the setting of labeling for blood-stream infections.

         In 1992, the FDA developed a document called Points to Consider.  This was a very important document because it was designed to assist investigators on how to formulate drug-development plans for infective agents.  Since that time, there have been several anti-infective drug advisory committee meeting where the issue has been discussed, including 1993, 1998 and 1999 and, obviously, at the meeting today.

         (Slide.)

         Just to give you a little bit of a perspective on the terminology that has been used for blood-stream infections in antimicrobial, I just have a chart to kind of compare the historical terminology versus what is used currently.  Historically, labels would include terms such as bacteremia or septicemia or bacteremia/septicemia, bacterial septicemia or septicemia (including bacteremia.)

         Today, what is used currently is terminology that is in accordance with the Points to Consider document which is basically site-specific indications with bacteremia included if bacteremic patients were involved and assessed adequately within the particular trials.

         To give you a little more perspective on the labeling indications prior to 1992, 1993, the terms "bacteremia" and "septicemia" were those that were used most commonly.